Possible involvement of nitric oxide in the lipopolysaccharide-induced impairment of hepatic mitochondrial respiration in vivo

LPS was injected into rats alone or in combination with an NO synthase inhi bitor, N-G-monomethyl-l-Arg, or a microsomal P450 inhibitor, SKF525A, and t hen respiration and phosphorylation in isolated liver mitochondria were mea sured to gain an insight into the mechanism underlying the LPS-induced mito chondrial injury. Mitochondrial respiration in the presence of ADP or 2,4-D NP was significantly reduced 10 h after injection of 10-15 mg/kg LPS, witho ut involving changes in state 4 respiration or the ADP/O ratio. Comparison of the respiration rates with three kinds of substrates, malate/glutamate, succinate and ascorbate/TMPD in mitochondria from control and LPS-treated r ats suggested that not only complex IV but also other components such as co mplexes I and II are injured by the LPS treatment. Injection of LPS caused an about 2-fold increase in microsomal lipid peroxides as well as massive N O production in the liver, but mitochondrial lipid peroxides were rather re duced. Both N-G-monomethyl-L-Arg and SKF525A were effective in preventing t he LPS-induced respiration injury, and the changes in NO production and the lipid peroxide level. Upon prolonged exposure of mitoplasts to FK409, an N O generator, succinate-cytochrome c reductase and cytochrome oxidase were i nactivated. It appears that NO, rather than lipid peroxides, plays a predom inant role in the LPS-induced impairment of mitochondrial respiration.